Biology subjects

Hall, M. A.

Publications and source records attributed to Hall, M. A..

4 recordsLinked to original sources

bioRxiv2026

MetScore and classical-basal subtype intersect to define chemotherapy response and tumor microenvironment architecture in pancreatic ductal adenocarcinoma

Background Transcriptomic heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is conventionally modeled along a single classical-basal axis, but this framework incompletely explains clinical behavior. We hypothesized that MetScore, a single-sample measure of metastatic colonization potential, defines a complementary axis. Objective To determine how MetScore and classical-basal identity jointly shape PDAC biology and clinical outcomes. Design We integrated RNA sequencing, DNA sequencing, clinical, and digital pathology data from 512 tumor biopsies from 510 patients in the Pancreatic Cancer Action Network Know Your Tumor real-world cohort. We assessed associations with biopsy site, survival, chemotherapy response, and tumor microenvironment composition; validated metastatic discrimination in an independent cohort; and examined cancer cell-intrinsic drug sensitivity in vitro. Results MetScore distinguished metastatic from primary biopsies, a finding validated externally. High MetScore and basal identity were independently associated with inferior survival. High MetScore and classical identity were each associated with preferential response to 5-fluorouracil (5-FU)-based rather than gemcitabine-based therapy, with the strongest enrichment for 5-FU responses among classical/MetScore-high patients. In vitro drug-sensitivity experiments did not recapitulate the clinical treatment-response pattern, motivating investigation of cancer cell-extrinsic factors. Transcriptomic deconvolution and histopathologic machine learning-based cell annotation demonstrated that high-MetScore and basal states converged on macrophage/monocyte enrichment but diverged in their associations with cancer-associated fibroblasts. Conclusion Integrating MetScore with classical-basal identity establishes a two-axis framework that better explains metastatic behavior, prognosis, treatment response, and microenvironmental composition than the conventional one-axis model and provides a clinically testable strategy for transcriptome-guided patient stratification.

cancer biology↗

bioRxiv2023

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell therapy

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease; [~]12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted outcomes in PDAC patients, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMM) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and cost of colony maintenance. We characterized the immunologic features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC models using two mouse cell lines, KPC-Luc and MT-5, isolated from KPC-GEMM mouse models (KrasLSL-G12D/+p53-/- and KrasLSL-G12D/+p53LSL-R172H/+, respectively). The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate KPC-Luc tumors, which have less stroma. Albeit CD4+ T cells were similarly detected in MT-5 tumors compared to KPC-GEMM in mice. Interestingly, we found that CAR T cells redirected to recognize mesothelin on these tumors that signal via CD3{sigma} and 41BB (Meso-41BB{sigma}-CAR T cells) post antigen recognition infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve in-depth study of how to overcome barriers that limit anti-tumor activity of adoptively transferred T cells.

cancer biology↗

bioRxiv2021

Gut microbial diversity in stingless bees is linked to host wing size and is influenced by geography

Stingless bees are globally important social corbiculate bees, fulfilling critical pollination roles in many ecosystems; however, their gut microbiota, especially fungal communities, are not well characterized to date. We collected 121 bee samples from two species, Tetragonula carbonaria and Austroplebeia australis, across a distance of 1,200 km of eastern Australia, and analysed their gut microbiomes. We found that the gut bacterial richness of T. carbonaria was influenced by geography (latitude and longitude) and positively correlated to an established fitness indicator in insects; namely, host forewing length/size that relates to flight capacity of stingless bees. We characterized the core microbiomes of the two bees and found that they consisted of the bacterial taxa Snodgrassella, Lactobacillus, Acetobacteraceae and Bombella, and the fungal taxa Didymellaceae, Monocilium mucidum, Malassezia restricta and Aureobasidium pullulans. Both host species identity and management (wild or managed) significantly influenced the gut microbial diversity and composition, and similarity between colonies declined as the geographical distance between them increased. This result was also supported by our co-existing network analyses. Overall, we have thoroughly analysed stingless bee gut microbiomes, and provided novel evidence that T. carbonaria bees with larger wings or from more southern populations have higher microbial diversity in their guts. Originality-Significance StatementBeneficial interactions between insects and their microbial symbionts are pivotal for their fitness. In this study, we analysed the gut microbiomes of two stingless bee species, Tetragonula carbonaria and Austroplebeia australis, that are widespread and important pollinators in Australia. We characterized their gut microbiomes and detected a significant positive correlation between gut bacterial richness and host forewing size for T. carbonaria; the first time that gut microbial diversity has been linked to a morphological trait in stingless bees. Furthermore, we found that host species identity, management type (wild or managed) and geography all significantly influenced bee gut microbial diversity and composition, and were able to describe both bacterial and fungal core microbial taxa. This study reveals novel understandings of stingless bee gut microbiomes and provides the basis for utilizing microbial strategies to maintain colony health.

ecology↗

bioRxiv2019

High sampling effectiveness for non-bee pollinators using vane traps in both open and wooded habitats

O_LINon-bee insects are important for pollination, yet few studies have assessed the effectiveness of sampling these taxa using low cost passive techniques, such as coloured vane traps, among different habitat types. C_LIO_LIThis study sampled 192 sites--108 in wooded and 84 in open habitats within an agricultural region of southern Australia. Pairs of blue and yellow vane traps were placed at each site for a period of seven days during the austral spring. C_LIO_LIOverall, 3114 flies (Diptera) from 19 families and 528 wasps (non-bee and non-formicid Hymenoptera) from 16 families were collected during the study. This sampling was representative of the region, with vane traps equally or more likely to collect as many families from both taxa as those reported on the Atlas of Living Australia (ALA) database for the sampling area. C_LIO_LIBlue vane taps (BVTs) had greater average richness of both flies and wasps and greater abundance of individuals than yellow vane traps (YVTs). BVTs were particularly favoured by certain fly and wasp families known to pollinate flowers (e.g. Syrphidae, Bombyliidae and Scoliidae), whilst YVTs sampled some less common fly families, such as Acroceridae and Bibionidae that also provide additional ecosystem services to pollination. C_LIO_LIVane traps are an effective passive sampling technique for non-bee pollinators, such as flies and wasps. This study supports the use of vane traps as a component of the sampling protocol for ecological census and population monitoring within multiple habitat types, to effectively sample a more complete pollinator community. C_LI

ecology↗